Metabolic syndrome, a western diet-induced, pro-inflammatory disease affecting up to 25% of Americans, is characterized by central obesity, impaired glucose tolerance, dyslipidemia, insulin resistance, and type II diabetes. Secondary complications associated with metabolic syndrome include atherosclerosis, stroke, fatty liver disease, blindness, gallbladder disease, cancer, polycystic ovary disease and others. Consequently there is interest in reducing food intake, losing weight, and reducing elevated blood glucose. There is also an interest in combating obesity and related conditions using methods that do not require drastic lifestyle or dietary changes. In addition, inflammatory gastrointestinal conditions resulting from various types of pathology affect millions of people. Thus, effective and targeted treatments for various inflammatory gastrointestinal (GI) conditions are also needed.
Farnesoid X receptor (FXR) is a ligand-activated transcriptional receptor expressed in diverse tissues including the adrenal gland, kidney, stomach, duodenum, jejunum, ileum, colon, gall bladder, liver, macrophages, and white and brown adipose tissue (Forman et al., Cell 81: 687-693 (1995). FXR has been reported to contribute to the regulation of whole body metabolism including bile acid/cholesterol, glucose and lipid metabolism. Synthetic ligands for FXR have been identified and applied to animal models of metabolic disorders, but these known synthetic ligands have shown limited efficacy and, in certain cases, exacerbated phenotypes.
Bile acids (BAs) function as endogenous ligands for FXR such that enteric and systemic release of BAs induces FXR-directed changes in gene expression networks (Lee et al., Trends Biochem Sci 31: 572-580, 2006; Repa et al., Science 289: 1524-1529, 2000; Zollner et al., J Hepatol 39: 480-488, 2003; Fang et al., J Biol Chem 283: 35086-35095, 2008; Kemper et al., Cell Metab 10: 392-404, 2009; Makishima et al., Science 284: 1362-1365, 1999; Stedman et al., Proc Natl Acad Sci USA 103: 11323-11328, 2006). The complex role of FXR in metabolic homeostasis is evident in studies on whole body FXR knockout (FXR KO) mice. On a normal chow diet, FXR KO mice develop metabolic defects including hyperglycemia and hypercholesterolemia, but conversely, exhibit improved glucose homeostasis compared to control mice when challenged with a high fat diet (Sinal et al., Cell 102: 731-744, 2000; Prawitt et al., Diabetes 60: 1861-1871, 2011). Similar contrary effects are seen with systemic FXR agonists, with beneficial effects observed when administered to chow-fed mice and exacerbated weight gain and glucose intolerance observed when administered to diet-induced obesity (DIO) mice (Zhang et al., Proc Natl Acad Sci USA 103: 1006-1011, 2006; Watanabe et al., J Biol Chem 286: 26913-26920, 2011).
In the liver, FXR activation suppresses hepatic BA synthesis, alters BA composition, reduces the BA pool size (Wang et al., Dev Cell 2: 721-731, 2002; Fang et al., Mol Cell Biol 27: 1407-1424, 2007; Lu et al., Mol Cell 6: 507-515, 2000), and contributes to liver regeneration (Huang et al., Science 312:233-236, 2006) as well as lipid and cholesterol homeostasis (Zhang et al., Genes Dev 18: 157-169, 2004; Ma et al., J Clin Invest 116: 1102-1109, 2006). Consistent with this, activation of hepatic FXR by the synthetic bile acid 6α-ethyl chenodeoxycholic acid (6-eCDCA) is beneficial in the treatment of diabetes, non-alcoholic fatty liver disease (NAFLD), and primary biliary cirrhosis (PBC) (Stanimirov et al., Acta Gastroenterol Belg 75: 389-398, 2012; Mudaliar et al., Gastroenterology 145: 574-582 e571, 2013).
FXR is also widely expressed in the intestine where it regulates production of the endocrine hormone FGF15 (FGF19 in humans), which, in conjunction with hepatic FXR, is thought to control BA synthesis, transport and metabolism (Kim et al., J Lipid Res 48: 2664-2672, 2007; Song et al., Hepatology 49: 97-305, 2009; Inagak et al., Cell Metab 2: 217-225, 2005). Intestinal FXR activity is also known to be involved in reducing overgrowth of the microbiome during feeding (Li et al., Nat Commun 4: 2384, 2013; Inagaki et al., Proc Natl Acad Sci USA 103: 3920-3925, 2006).